11/11/2022 0 Comments Bt474 clone 5 apotox glo assayIn this role, PARP1 binds damaged DNA and this interaction stimulates auto-PARsylation of PARP1 and trans-PARsylation of additional DNA repair mediators such as XRCC1 and chromatin structure proteins such as histones. Of the 17 or so PARP superfamily members, PARP1 is the most studied, and is known, amongst other functions, to play a critical role in DNA repair. PARP enzymes add ADP-ribose moieties onto proteins, using β-NAD + as substrate. PARsylation is catalysed by a series of structurally related proteins, the poly(ADP) ribose polymerase (PARP) superfamily. The addition of poly(ADP-ribose) chains onto proteins (PARsylation) is a post-translational modification that has been implicated in a wide range of biological processes as diverse as the maintenance of genomic stability (Hottiger et al, 2010) and Wnt signalling (Callow et al, 2011 Huang et al, 2009 Zhang et al, 2011). Importantly, inhibition of NAMPT can increase the in vitro and in vivo effects of olaparib in models of triple-negative breast cancer, a subtype of particular unmet clinical need.Īs both small molecule NAMPT and PARP inhibitors are currently in clinical development, these observations highlight the potential for using combination therapy that involves modulators of β-NAD + metabolism. NAMPT catalyses a rate limiting step in the generation of the PARP substrate β-NAD +, suggesting a likely mechanism of action for these effects. Here, we show that targeting of the β-NAD + metabolism enzyme NAMPT can increase the tumour cell inhibitory effect of the clinical PARP inhibitor olaparib. However, it is not yet clear as to whether single agent PARP inhibitor therapy or combination therapy using these drugs would be most beneficial. PARP inhibition represents a promising therapeutic approach for cancer. Importantly, the combination of a NAMPT small molecule inhibitor, FK866, with olaparib inhibited TN breast tumour growth in vivo to a greater extent than either single agent alone suggesting that assessing NAMPT/PARP inhibitor combinations for the treatment of TN breast cancer may be warranted. NAMPT is a rate-limiting enzyme involved in the generation of the PARP substrate β-NAD + and the suppression of β-NAD + levels by NAMPT inhibition most likely explains these observations. Using an olaparib sensitization screen in a triple-negative (TN) breast cancer model, we identified nicotinamide phosphoribosyltransferase (NAMPT) as a non-redundant modifier of olaparib response. To better understand the mechanisms that determine the response to PARP inhibitors, we investigated whether enzymes involved in metabolism of the PARP substrate, β-NAD +, might alter the response to a clinical PARP inhibitor. However, it is as yet unclear as to whether single agent or combination therapy using PARP inhibitors would be most beneficial. PARP inhibitors have been proposed as a potential targeted therapy for patients with triple-negative (ER-, PR-, HER2-negative) breast cancers.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |